Elucidating the role of IL-2 in the brain during development could have important implications for understanding processes involved in autoimmune diseases affecting the brain, as well as neurodevelopmental diseases such as schizophrenia. This proposal will test the hypothesis that deletion of the IL-2 gene in the CNS produces spatial learning deficits resulting from alterations in hippocampal neurodevelopment and function. IL-2 mRNA transcripts and IL-2-like immunoreactivity have been identified in rodent and human brain and IL-2 has been implicated as both a neurotrophic factor and neuromodulator. To determine how and where IL-2 works in the brain, we have cloned and sequenced the full-length cDNAs for the alpha, beta, and gamma subunits of the brain IL-2 receptor complex. Our data and the work of others show that IL-2 receptor gene expression is enriched in the hippocampal formation, which is the only brain region where specific IL-2 receptor binding has been detected. Our preliminary studies using IL-2 knockout mice are the first to demonstrate that IL-2 gene deletion produces robust impairments in spatial learning. Thus, we propose to characterize the nature of the learning impairment in IL-2 knockout mice, focusing on the effects of IL-2 gene deletion on the neurodevelopment and function of the hippocampus. The specific aims will: 1) Characterize the neurobehavioral phenotype resulting from IL-2 gene deletion, 2) Test the hypothesis that the neurobehavioral phenotype of IL-2 knockout mice results principally from the absence of the IL-2 gene in the CNS, rather than in the periphery, and 3) Test the hypothesis that the spatial learning deficit produced by IL-2 gene deletion will be accompanied by alterations in hippocampal cytoarchitecture and neurobiology. The proposed studies will be the first to determine the consequences of the absence of IL-2 on these aspects of brain development and behavior. We believe that the proposed research is timely and will lay an essential foundation on which to build in future studies.